Intracranial microdialysis has been performed in human patients since the 1970s but has not yet been adopted or approved as a diagnostic technology. There is an urgent need for enhanced microdialysis technology with diagnostic capabilities. Microdialysis is the only existing technology with the demonstrated ability to detect two key chemical markers, glucose and potassium ion, of secondary brain injury in patients with severe traumatic brain injury. Diagnosis of secondary injury is critical because it is a major contributor to poor outcomes (severe disability, vegetative state, and death) even for patients who survive their injury, surgery, and several days of intensive care. Until recently, gliosis at the probe track has severely limited the performance capabilities of microdialysis. Adding dexamethasone to the perfusion fluid, however, has proven a simple yet highly effective approach to suppressing gliosis. Dexamethasone has enabled us to recently detect aberrations of glucose and potassium in the cortex of the rat brain 11 days after inducing an injury by controlled cortical impact. Herein, we propose to explore three additional novel and significant technical enhancements for intracranial microdialysis that build on our recent successes. First, we propose to explore nano-scale modifications of the dialysis membrane as an alternative to dexamethasone, because circumstances may arise that preclude the use of dexamethasone. Second, we propose to explore glucose delivery as a means to reverse glucose deficits in the rat brain after controlled cortical impact: this work will establish the foundation for a novel therapy for secondary brain injury. Third, in a search for novel chemical markers for secondary injury, we will explore mass spectrometric analysis of brain dialysate as a source of orthogonal chemical information from the brain.